Lifespan in the nematode, C. elegans, is determined by interacting genetic pathways as well as by environmental conditions. For example, mutations in the daf-2/insulin-like signaling pathway nearly triple adult lifespan. One goal of this project is to learn why these mutants live longer. It has been shown that insulin signaling must be active in the C. elegans nervous system for normal lifespan, suggesting that neurons somehow control lifespan. To determine how neurons control lifespan, we are isolating mutant animals that live shorter or longer than the long-lived insulin pathway mutants. These mutants will enable us (a) to identify the genes that are required for a long adult lifespan and (b) to identify previously unknown pathways that influence adult lifespan. Many basic biological processes are shared between nematodes and humans. Therefore, some of the genes that control lifespan in the worm may also have human versions that perform similar functions. Recently, we have succeeded isolating candidate mutants from these studies. A second goal of this project is to identify genes required for successful aging in the nervous system. Successful aging in humans can be thought of as increasing resistance to aging-associated neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. We have begun by characterizing how the C. elegans nervous system changes during aging. We have found that there are three stages to nematode adulthood: a reproductive phase, a mid-life phase and a late-life phase that preceeds death. The most dramatic aging-associated changes occur in the mid-life phase, and these may involve changes in neurotransmitter activity. We are currently studying why the neurotransmitter activity appears to change in the mid-life stage. These studies of aging in the relatively simple organism, C. elegans, will provide a stepping stone for understanding the more complex processes that control human aging and lifespan.